1. Field of Invention
The present invention describes a system and method for performing in vivo blood analysis. This is accomplished by directing a probe beam, consisting of monochromatic, coherent, polarized, quantum state entangled, exclusive or nearly exclusive co-incident photons, at the conjunctiva and its blood vessels of a patient and analyzing the resulting conventional Raman backscatter spectrum and the changes in the quantum state characteristics of the entangled photons.
2. Background of the Invention
Various blood chemistry and hematology tests are available to obtain a great amount of information about a patient's physical condition. These results, after review and interpretation, play an important part in an overall diagnosis. However, all these tests require actual samples taken from a patient. Of course, the process of drawing blood, can be uncomfortable, and even painful, especially if constant repetitive sampling is necessary as in the case of diabetics.
For this reason non-invasive in vivo blood studies by optical devices and methods have been investigated with great interest. The determination of an analyte, or a disease state, in a human subject without performing an invasive procedure, such as removing a sample ,of blood or a biopsy specimen, has several advantages. These advantages include ease in performing the test, reduced pain and discomfort to the patient, decreased exposure to potential biohazards, and no production of medical waste. These advantages encourage increased frequency of testing when necessary, accurate monitoring and control, and improved patient care. Representative examples of non-invasive monitoring techniques include pulse oximetry for oxygen saturation (U.S. Pat. Nos. 3,638,640; 4,223,680; 5,007,423; 5,277,181; 5,297,548). Another example is the use of laser Doppler flowmetry for diagnosis of circulation disorders (Toke et al, “Skin microvascular blood flow control in long duration diabetics with and without complication”, Diabetes Research, Vol. 5 (1987), pages 189–192). Other examples of techniques include determination of tissue oxygenation (WO 92/20273), determination of hemoglobin (U.S. Pat. No. 5,720,284) and of hematocrit (U.S. Pat. Nos. 5,553,615; 5,372,136; 5,499,627; WO 93/13706). These involve the use of transmission, or absorption spectroscopy.
Another type of phenomena can also be used for patient testing. This involves the way in which light scatters off any surface. That is to say, when light of any wavelength impinges on a surface (or molecule), most of the scattered photons are elastically (or Rayleigh) scattered. That means that they leave with the same frequency (or wavelength) as the incident radiation. In contrast to this there is a small fraction of the scattered light (less than one in a thousand incident photons) that is inelastically (or Raman) scattered at frequencies that differ from the incident frequency by a value determined by the molecular vibrations of the sample. Raman scattering creates a discrete atomic or molecular spectrum at frequencies corresponding to the incident frequency plus or minus the atomic or molecular vibrational frequency. A Raman spectrum is thus a plot of the intensity of scattered light as a function of frequency (or wavelength). By convention, Raman spectra are shown on an orthogonal graph with the wave numbers (reciprocal centimeters) along the horizontal axis and the abscissa representing intensity or energy.
Raman spectra have long been used to determine the structure of inorganic and biological molecules, including the composition of complex multicomponent samples. Raman spectroscopy is considered to have many advantages as an analytical technique. Most strikingly, it provides vibrational spectra that act as an atomic o,r molecular fingerprint containing, unique, highly reproducible, detailed features, thereby providing the possibility of highly selective determinations.
In comparing Raman scattering verses other forms of analysis, the Raman approach is advantageous for several reasons:
1. Solid, liquid and gas states can be analyzed.
2. Aqueous solutions present no special problems.
3. No special pre-scanning preparation of the sample is necessary.
4. The low frequency region is easily obtained.
5. The device can be made inexpensive lightweight and portable.
6. Scanning can be completely non invasive or even clandestine.
7. Scanning distance can be varied from centimeters to kilometers.
Several previous inventors have recognized the potential for using Raman scattering as a non-invasive (NI) sensor for scanning individuals. U.S. Pat. No. 6,574,501 discusses assessing blood brain barrier dynamics or measuring selected substances or toxins in a subject by analyzing Raman spectrum signals of selected regions in aqueous fluid of the eye. U.S. Pat. No. 5,553,616 discloses the use of Raman scattering with excitation in the near infrared (780 nm) and an artificial neural network for measuring blood glucose. WO 92/10131 discusses the application of stimulated Raman spectroscopy for detecting the presence of glucose. U.S. Pat. No. 6,070,093, describes a noninvasive glucose sensor that combines Raman measurements with complementary non-invasive techniques in order to enhance the sensitivity and selectivity of the measurement.
Other previous inventors have recognized the potential for using Raman scattering for non-invasively scanning of objects. U.S. Pat. No. 6,608,677 discloses the use of a Mini-lidar sensor for the remote stand-off sensing of chemical/biological substances and method for sensing same. U.S. Pat. No. 6,593,582 discloses a Portable digital lidar system, which in part could use raman backscattering. U.S. Pat. No. 4,802,761 discusses optical-fiber Raman spectroscopy used for remote in-situ environmental analysis.
Still other previous inventors have recognized the potential for using SPDC (Spontaneous Parametric Down Converstion) photons for enhancing the scanning of objects. U.S. Pat. No. 5,796,477 discloses an entangled-photon microscope, for waveform fluorescence microscopy.
A major challenge for all of the Raman techniques to date has been to collect spectral information with sufficiently high signal-to-noise ratios to discriminate weak analyte signals from the underlying background noise.
Existing non-invasive in vivo Raman measurements are hindered by a number of factors, including notoriously low quantum efficiency. In other words, very few inelastic scattering events occur in comparison to the number of elastic scattering events. Conventionally, in non-resonance Raman spectroscopy in order to double the efficiency of Raman scattering it is necessary to square the photon density. Unfor-tunately this can damage the sample. Therefore it is necessary to perform scans at either long integration times or high power densities to achieve acceptable signal-to-noise (S/N) ratios.
Other forms of Raman scattering like, resonance and surface enhancement can significantly improve the sensitivity and selectivity of Raman measurements. However, these enhancements are not generally applicable to all analytes or to all samples, especially in vivo. Furthermore relating band intensities to analyte concentrations under such circumstances requires careful calibration procedures.